Proximal Threats Promote Enhanced Acquisition and Persistence of Reactive Fear-Learning Circuits
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Proximal threats promote enhanced acquisition and persistence of reactive fear-learning circuits Leonard Faula,1, Daniel Stjepanovica,b,1, Joshua M. Stiversa, Gregory W. Stewarta, John L. Granera, Rajendra A. Moreyc, and Kevin S. LaBara,c,2 aDepartment of Psychology & Neuroscience, Duke University, Durham, NC 27708; bCentre for Youth Substance Abuse Research, The University of Queensland, St Lucia, QLD 4072, Australia; and cDepartment of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710 Edited by Joseph E. LeDoux, New York University, New York, NY, and approved June 1, 2020 (received for review March 6, 2020) Physical proximity to a traumatic event increases the severity of similar set of regions initially active during the learning period accompanying stress symptoms, an effect that is reminiscent of (9, 10). evolutionarily configured fear responses based on threat immi- The development of neurocognitive models for conditioned nence. Despite being widely adopted as a model system for stress fear learning provides a promising means to better understand and anxiety disorders, fear-conditioning research has not yet char- psychiatric symptoms of threat hypersensitivity and fear persis- acterized how threat proximity impacts the mechanisms of fear tence, as exemplified by posttraumatic stress disorder (PTSD) acquisition and extinction in the human brain. We used three- (11, 12). However, most fear-conditioning studies rely on brief dimensional (3D) virtual reality technology to manipulate the ego- presentations of images or sounds as conditioned stimuli, a centric distance of conspecific threats while healthy adult partici- method that is well-suited for the constraints of traditional re- pants navigated virtual worlds during functional magnetic search settings but difficult to generalize to many real-life trau- resonance imaging (fMRI). Consistent with theoretical predictions, matic encounters. In recent years, the development of virtual proximal threats enhanced fear acquisition by shifting conditioned reality (VR) has offered a promising means by which to address learning from cognitive to reactive fear circuits in the brain and this limitation, as it affords a richer experimental manipulation – reducing amygdala cortical connectivity during both fear acquisi- of both threat cues and contexts, and ultimately provides a more tion and extinction. With an analysis of representational pattern salient and ecologically valid experience (13). VR technology is similarity between the acquisition and extinction phases, we fur- especially powerful for manipulating spatial distance, which sig- PSYCHOLOGICAL AND COGNITIVE SCIENCES ther demonstrate that proximal threats impaired extinction effi- nificantly contributes to the severity of trauma-related disorders, cacy via persistent multivariate representations of conditioned but has yet to be incorporated into existing fear-conditioning learning in the cerebellum, which predicted susceptibility to later models. Compared to spatially distal events, traumatic events fear reinstatement. These results show that conditioned threats encountered in close proximity are more resistant to extinction that directly involve the body envelope, such as rape and assault, learning and suggest that the canonical neural circuitry typically are most strongly associated with PTSD (14), and a systematic associated with fear learning requires additional consideration of review showed that direct exposure and close proximity to an a more reactive neural fear system to fully account for this effect. Significance proximity | fear conditioning | virtual reality | representational similarity analysis | cerebellum Traditional laboratory-based fear-conditioning approaches are often limited in their generalizability to real-world encounters ecognizing potential threats is a fundamental survival skill where threats are dynamic and embedded in contextually rich Rthat enables the appropriate selection of defensive behaviors environments. Moreover, while spatial distance to a threat (1, 2). Given the importance of this evolutionarily configured organizes defensive responses, our understanding of the neu- response, researchers have long studied the underlying processes robehavioral mechanisms relating proximity and fear learning that support the learning of threat associations. These paradigms is lacking. To address these limitations, we developed a three- dimensional (3D) virtual reality simulation that provides a more typically place a conditioned stimulus (CS) in a predictive re- ecologically valid examination of how threat proximity influ- lationship with an aversive reinforcer, and then test for the ences the learning and memory of fear associations. Our find- persistence of the acquired defensive response when it is no ings highlight that threats invading peripersonal space persist longer reinforced (3). A dynamic neural system supports the longer in memory and uniquely recruit a reactive neural fear acquisition and extinction of threat associations, involving bi- system, which has important clinical implications for un- directional connections among prefrontal, medial temporal, and derstanding how near-body traumatic experiences exacerbate midbrain structures (4). Specifically, the prevailing neural ac- the development of traumatic stress disorders. count highlights the importance of the amygdala in receiving sensory information and generating defensive behavior (5), the Author contributions: D.S., R.A.M., and K.S.L. designed research; L.F., D.S., J.M.S., and hippocampus in storing memory representations for fearful G.W.S. performed research; L.F., J.M.S., and J.L.G. analyzed data; and L.F., D.S., J.L.G., R.A.M., and K.S.L. wrote the paper. contexts (6), and dorsal and ventral portions of the medial pre- The authors declare no competing interest. frontal cortex (mPFC) in facilitating fear expression or sup- This article is a PNAS Direct Submission. pression, respectively (7). Moreover, while detailing this general shared network supporting conditioned fear learning, re- Published under the PNAS license. Data deposition: Behavioral and psychophysiological data are available at Open Science searchers have also examined important modulatory factors that Framework (https://osf.io/jm62y/). Unthresholded statistical maps are available at expand our understanding of the complex neural architecture NeuroVault (https://neurovault.org/collections/6221/). underlying the initial acquisition and long-term maintenance of 1L.F. and D.S. contributed equally to this work. threat associations. For example, such investigations have in- 2To whom correspondence may be addressed. Email: [email protected]. dicated dissociable roles for the amygdala and hippocampus in This article contains supporting information online at https://www.pnas.org/lookup/suppl/ cue and context-related fear conditioning, respectively (8), and doi:10.1073/pnas.2004258117/-/DCSupplemental. that fear generalization to perceptually related stimuli engages a www.pnas.org/cgi/doi/10.1073/pnas.2004258117 PNAS Latest Articles | 1of12 Downloaded by guest on September 26, 2021 event increases the risk of PTSD development and number of predators, reflecting temporal proximity (32). Participants were associated symptoms (15). Moreover, spatial proximity to a motivated to flee from a virtual predator as late as possible in highly traumatic bank robbery has been found to be a risk factor order to acquire more money, thus requiring consideration of the for PTSD diagnosis 1 mo later, and this relationship is mediated distance to the threat, the cost of fleeing, and the cost of staying. by acute stress up to 2 d following the robbery (16). Yet, while Qi et al. (32) found faster-attacking predators elicit a reactive such emerging evidence suggests strong long-term modulatory fear circuit comprising the midbrain and midcingulate cortex effects of spatial proximity on fear circuitry, no study to our (MCC) that facilitates rapid escape decisions, whereas slower- knowledge has directly assessed how proximity to a conditioned attacking predators resulted in activation of fear circuitry im- threat influences conditioned-learning circuits in the human plicated in cognitive appraisals and associative learning, in- brain and subsequent reactivity to threat stimuli. cluding the vmPFC, hippocampus, and posterior cingulate cortex Findings from nonhuman animals suggest that a relationship (PCC). The differential recruitment of reactive and cognitive between proximity and fear learning stems evolutionarily from fear circuitry was also associated with optimal escape decisions predator–prey interactions, whereby a prey’s behavior shifts from derived from a Bayesian model, emphasizing the SOS proposal a strategic to a reactionary defensive state based on distance to a of adaptive shifts between fear circuitry that helps to adjust be- predator (17). According to the predatory imminence contin- havior (1). These findings have provided compelling evidence for uum, this effect can be understood along three primary phases: dissociation in the neural circuitry supporting threat responses, al- 1) A preencounter phase that configures behaviors to minimize though the differential recruitment of cognitive and reactive fear contact with a potential threat (e.g., adjusting meal patterns), 2) circuits have yet to be incorporated in neurocognitive models for a postencounter phase after predator detection that elicits the learning and long-term memory of threat associations.